Assessing and improving bone quality in chronic kidney disease

 描述(申请人提供)：慢性肾脏疾病-矿物质和骨骼障碍(CKD-MBD)患者骨折风险增加，骨折相关死亡率更高，并且由于CKD的代谢复杂性而难以治疗。此外，监测骨折风险(即骨密度，BMD)的标准做法在这类患者群体中存在局限性。目前，CKD-MBD患者的治疗主要集中在抑制甲状旁腺激素升高，这可以通过类钙剂来完成。Cinacalcet是FDA批准的一种仿钙剂，有效地降低了甲状旁腺激素，减缓了骨转换，增加了骨量，但仅适度地降低了骨折风险。这表明，骨质量的缺陷，而不仅仅是骨丢失，是导致CKD脆性的原因，最近有证据表明，CKD骨中胶原交联和基质水合的变化支持了这一观点。为这项研究收集的初步数据发现了骨微损伤的证据，这是另一个以前在CKD中未被研究的骨质量的重要因素。已知微损伤与孔隙率相互作用，因此这些问题的结合可能会对CKD的脆弱性产生重大影响。总而言之，使这些患者的骨折风险正常化可能不只是简单地抑制骨丢失，还必须治疗骨质量。我们假设CKD的骨质量可以通过联合应用拟钙剂来减少甲状旁腺激素和骨丢失，而雷洛昔芬是一种选择性的雌激素受体调节剂，最近被发现对骨组织质量有直接的积极作用。我们将使用CKD-MBD的缓慢进展模型--Cy/+大鼠来检验这一假设。这项研究将首先量化30周龄和35周龄CKD大鼠骨骼微损伤的程度，并与它们正常的、年龄匹配的小鼠进行比较。我们预计CKD会导致皮质孔隙度和微损伤的积累逐渐增加，微裂缝和孔隙率之间发生相互作用。接下来，将测试拟钙剂和雷洛昔芬联合治疗改善骨量和质量指标的能力。CY/+大鼠从25周龄到35周龄将用赋形剂、雷洛昔芬、拟钙剂或两者兼用。主要结果将通过骨骼分析(微损伤、组织学、显微CT、骨密度、力学测试和抗疲劳能力)来确定，尽管治疗对CKD-MBD的生化和肾脏成分的影响也将被评估。我们预测雷洛昔芬将通过改善骨质量和减少微损伤形成来改善骨的力学性能，而拟钙治疗将通过增加骨量和减少孔隙率来改善力学性能。联合治疗应该通过对质量和质量的积极影响而超过两种单一治疗。了解CKD对骨质量的不利影响是预防这些患者骨折的关键一步。这项研究通过检测CKD自发和进行性发展的大鼠模型中的这些变化及其潜在的纠正，为实现这一目标提供了重要的一步。

 DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) patients have increased fracture risk, have a higher risk of fracture-related mortality, and are difficult to treat due to CKD's metabolic complexity. Furthermore, standard practices for monitoring fracture risk (i.e. bone mineral density, BMD) have limitations in this patient population. Currently, treatment for CKD-MBD patients is primarily focused on suppressing elevated parathyroid hormone, as can be accomplished with a calcimimetic. Cinacalcet, an FDA approved calcimimetic, effectively reduces parathyroid hormone, slows bone turnover and increases bone mass, yet it only modestly reduces fracture risk. This suggests a defect in bone quality, not just bone loss, is contributing to CKD fragility, and this notion is supported by recent evidence of alterations in collagen cross-linking and matrix hydration in CKD bone. Preliminary data collected for this study found evidence of bone microdamage, another important factor of bone quality which is previously unstudied in CKD. Microdamage is known to interact with porosity, thus the combination of these issues may have significant impact on CKD fragility. In summary, normalizing fracture risk in these patients will likely require more than simply suppressing bone loss; the bone quality must also be treated. We hypothesize that the quality of CKD bone can be improved using a combination treatment of calcimimetic, to reduce parathyroid hormone and bone loss, and raloxifene, a selective estrogen receptor modulator drug for osteoporosis recently revealed to have direct positive effects on bone tissue quality. We will test this hypothesis using a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will first quantify the extent of skeletal microdamage in the bones of 30 and 35-week old CKD rats in comparison to their normal, age-matched littermates. We expect CKD to cause progressively increasing accumulation of cortical porosity and microdamage, with interactions occurring between microcracks and porosity. Next, the ability of combination calcimimetic and raloxifene treatment to improve measures of bone quantity and quality will be tested. Cy/+ rats will be treated from 25 to 35 weeks of age with vehicle, raloxifene, calcimimetic, or both drugs. Primary outcomes will be determined by skeletal analyses (microdamage, histology, microCT, bone density, mechanical testing, and resistance to fatigue), though the treatments' effects on the biochemical and renal components of CKD-MBD will be assessed as well. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality and reducing microdamage formation, while calcimimetic treatment will improve mechanical properties by increasing bone mass and reducing porosity. Combination therapy should exceed both single treatments by positively impacting both quality and mass. An understanding of the detrimental impact of CKD on bone quality is a crucial step in preventing fractures in these patients. This study provides an important step in achieving this goal by examining these changes and their potential corrections in a rat model with spontaneous and progressive development of CKD.